EP1979374A2 - Schablonenfixierte peptidomimetika - Google Patents

Schablonenfixierte peptidomimetika

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Publication number
EP1979374A2
EP1979374A2 EP07700115A EP07700115A EP1979374A2 EP 1979374 A2 EP1979374 A2 EP 1979374A2 EP 07700115 A EP07700115 A EP 07700115A EP 07700115 A EP07700115 A EP 07700115A EP 1979374 A2 EP1979374 A2 EP 1979374A2
Authority
EP
European Patent Office
Prior art keywords
lower alkyl
chr
alkenyl
alkyl
conr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP07700115A
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English (en)
French (fr)
Other versions
EP1979374B1 (de
Inventor
Frank Gombert
Daniel Obrecht
Wim Vrijbloed
Ricardo Dias
Steve J. Demarco
John Anthony Robinson
Nityakalyana Srinivas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zurich Universitaet Institut fuer Medizinische Virologie
Spexis AG
Original Assignee
Polyphor AG
Zurich Universitaet Institut fuer Medizinische Virologie
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Application filed by Polyphor AG, Zurich Universitaet Institut fuer Medizinische Virologie filed Critical Polyphor AG
Priority to PL07700115T priority Critical patent/PL1979374T3/pl
Priority to SI200730882T priority patent/SI1979374T1/sl
Publication of EP1979374A2 publication Critical patent/EP1979374A2/de
Application granted granted Critical
Publication of EP1979374B1 publication Critical patent/EP1979374B1/de
Priority to CY20121100294T priority patent/CY1117252T1/el
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention provides template-fixed ⁇ -hairpin peptidomimetics incorporating a template-fixed chain of 12 ⁇ -amino acid residues which, depending on their positions in the chain, are GIy or Pro, or of certain types, as defined herein below. These template-fixed ⁇ - hairpin mimetics have a selective antimicrobial activity.
  • the present invention provides efficient synthetic processes by which these compounds can, if desired, be made in parallel library-format.
  • These ⁇ -hairpin peptidomimetics show improved efficacy, bioavailability, half-life and most importantly a significantly enhanced ratio between antibacterial activity on the one hand, and hemolysis of red blood cells on the other.
  • tachyplesins [T. Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M. Niwa, T. Takao, Y. Shimonishi, Y. J. Biol. Chem. 1988, 263, 16709-16713], and the defensins [R. I. Lehrer, A. K. Lichtenstein, T. Ganz, Annu. Rev. Immunol. 1993, 11, 105-128], amphipathic ⁇ -helical peptides (e.g. cecropins, dermaseptins, magainins, and mellitins [A. Tossi, L.
  • cationic peptides such as protegrin 1 (A. Aumelas, M. Mangoni, C. Roumestand, L. Chiche, E.
  • Gramicidin S is a backbone-cyclic peptide with a well defined ⁇ -hairpin structure (S. E. Hull, R. Karlsson, P. Main, M. M. Woolfson, E. J. Dodson, Nature 1978, 275, 206-275) that displays potent antimicrobial activity against gram-positive and gram-negative bacteria (L. H. Kondejewski, S. W. Farmer, D. S. Wishart, R. E. Hancock, R. S. Hodges, Int. J. Peptide Prot. Res. 1996, 47, 460-466).
  • the high hemolytic activity of gramicidin S has, however, hindered its widespread use as an antibiotic.
  • protegrin analogues such as IB367 (J. Chen, T. J. Falla, H. J. Liu, M. A. Hurst, C. A. Fujii, D. A. Mosca, J. R. Embree, D. J. Loury, P. A. Radel, C. C. Chang, L. Gu, J. C. Fiddes,
  • protegrin 1 This broad antimicrobial activity combined with a rapid mode of action, and their ability to kill bacteria resistant to other classes of antibiotics, make them attractive targets for development of clinically useful antibiotics.
  • the activity against gram-positive bacteria is typically higher than against gram- negative bacteria.
  • protegrin 1 also exhibits a high hemolytic activity against human red blood cells, and hence a low selectivity towards microbial cells.
  • Oriented CD experiments W. T. Heller, A. J. Waring, R. I. Lehrer, H. W. Huang, Biochemistry 1998, 37, 17331- 17338) indicate that protegrin 1 may exist in two different states as it interacts with membranes, and these states are strongly influenced by lipid composition.
  • Studies of cyclic protegrin analogues J.-P. Tam, C.
  • Protegrin 1 is an 18 residues linear peptide, with an amidated carboxyl terminus and two disulfide bridges.
  • Tachyplesin I contains 17 residues, also has an amidated carboxyl terminus and contains two disulfide bridges.
  • Recently described backbone-cyclic protegrin and tachyplesin analogues typically contain 18 residues and up to three disulfide bridges (J. P. Tam, C. Wu, J.-L. Yang, Eur. J. Biochem. 2000, 267, 3289-3300; J. P. Tam, Y.-A. Lu, J.-L. Yang, Biochemistry 2000, 39, 7159-7169; N. Sitaram, R. Nagaraij, Biochem. Biophys. Res. Comm. 2000, 267, 783-790).
  • Cathelicidin a 37-residue linear helical-type cationic peptide, and analogues are currently under investigation as inhaled therapeutic agents for cystic fibrosis (CF) lung disease
  • CF cystic fibrosis
  • pseudomonas aeruginosa C. A. Demko, P. J. Biard, P. B. Davies, J. Clin.
  • a new strategy is introduced to stabilize ⁇ -hairpin conformations in backbone-cyclic cationic peptide mimetics exhibiting selective antimicrobial activity. This involves transplanting the cationic and hydrophobic hairpin sequence onto a template, whose function is to restrain the peptide loop backbone into a hairpin geometry.
  • the methods described herein allow the synthesis and screening of large hairpin mimetic libraries, which in turn considerably facilitates structure-activity studies, and hence the discovery of new molecules with potent selective antimicrobial and very low hemolytic activity to human red blood cells.
  • the present strategy allows to synthesize ⁇ -hairpin peptidomimetics with novel selectivities towards various multi-drug resistant pseudomonas- strains.
  • ⁇ -hairpin peptidomimetics of the present invention are compounds of the general formula
  • R 1 is H; lower alkyl; or aryl-lower alkyl
  • R 2 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ;
  • R 3 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ;
  • R 4 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ;
  • R 5 is alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ;
  • R 6 is H; alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ;
  • R 7 is alkyl; alkenyl; -(CH 2 ) q (CHR 61 ) s OR 55 ; -(CH 2 ) q (CHR 61 ) s NR 33 R 34 ;
  • R 8 is H; Cl; F; CF 3 ; NO 2 ; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;
  • R 9 is alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ;
  • R 10 is alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ;
  • R 11 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 6I ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s NR 33 R 34 ;
  • R 12 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ;
  • R 13 is alkyl; alkenyl; -(CH 2 ) q (CHR 61 ) s OR 55 ; -(CH 2 ) q (CHR 61 ) s SR 56 ;
  • R 14 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; -(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; -(CH 2 ) q (CHR 61 ) s COOR 57 ; -(CH 2 ) q (CHR 61 ) s CONR 58 R 59 ; -(CH 2 ) q (CHR 61 ) s PO(OR 60 ) 2 ; -(CH 2 ) q (CHR 61 ) s SO 2 R 62 ; or -(CH 2 ) q (CHR 6I ) s C 6 H 4 R 8 ;
  • R 14 is H; al
  • R 15 is alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 6I ) S NR 33 R 34 ;
  • R 16 is alkyl; alkenyl; -(CH 2 ) O (CHR 6! ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 61 ) S NR 33 R 34 ;
  • R 17 is alkyl; alkenyl; -(CH 2 ) q (CHR 61 ) s OR 55 ; -(CH 2 ) q (CHR 6I ) s SR 56 ; -(CH 2 ) q (CHR 61 ) s NR 33 R 34 ;
  • R 18 is alkyl; alkenyl; -(CH 2 ) P (CHR 6I ) S OR 55 ; -(CH 2 ) P (CHR 61 ) S SR 56 ; -(CH 2 ) P (CHR 6I ) S NR 33 R 34 ;
  • R 19 is lower alkyl; -(CH 2 ) P (CHR 61 ) S OR 55 ; -(CH 2 ) P (CHR 61 ) S SR 56 ; -(CH 2 ) P (CHR 61 XNR 33 R 34 ; -(CH 2 ) P (CHR 61 ) S OCONR 33 R 75 ; -(CH 2 )P(CHR 61 XNR 20 CONR 33 R 82 ; -(CH 2 ) P (CHR 61 XCOOR 57 ; -(CH 2 ) P (CHR 61 XCONR 58 R 59 ; -(CH 2 ) P (CHR 61 XPO(OR 60 ) 2 ; -(CH 2 ) P (CHR 61 X SO 2 R 62 ; or -(CH 2 ) O (CHR 61) s C 6 H 4 R 8 ; or R 18 and R 19 taken together can form: -(CH 2 ) 2
  • R 20 is H; alkyl; alkenyl; or aryl-lower alkyl;
  • R 21 is H; alkyl; alkenyl; -(CH 2 ) 0 (CHR 6I ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 61 ) S NR 33 R 34 ;
  • R 22 is H; alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 61 ) S NR 33 R 34 ;
  • R 23 is alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 61 ) S NR 33 R 34 ;
  • R 24 is alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 61 ) S NR 33 R 34 ;
  • R 25 is H; alkyl; alkenyl; -(CH 2 ) ffl (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ; -(CH 2 ) m (CHR 61 XNR 33 R 34 ; -(CH 2 ) m (CHR 61 ) 5 OCONR 33 R 75 ; -(CH 2 ) m (CHR 61 ) NR 20 CONR 33 R 82 ; -(CH 2 ) o (CHR 61 ) s COOR 57 ; -(CH 2 ) 0 (CHR 61 XCONR 58 R 59 ; -(CH 2 ) 0 (CHR 61 XPO(OR 60 ) 2 ; -(CH 2 ) O (CHR 61 XSO 2 R 62 ; or -(CH 2 ) O (CHR 61 ) S C 6 H 4 R
  • R 26 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ; -(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; -(CH 2 ) m (CHR 61 ) NR 20 CONR 33 R 82 ; -(CH 2 ) o (CHR 61 ) s COOR 57 ; -(CH 2 ) 0 (CHR 61 ) S CONR 58 R 59 ; -(CH 2 ) 0 (CHR 61 XPO(OR 60 ) 2 ; -(CH 2 ) O (CHR 61 ) S SO 2 R 62 ; or -(CH 2 ) O (CHR 61 ) S C
  • R 25 and R 26 taken together can form: -(CH 2 ) 2 . 6 -; -(CH 2 ) r O(CH 2 ) r -; -(CH 2 ) r S(CH 2 ) r -; or -(CH 2 ) r NR 57 (CH 2 ) r -;
  • R 27 is H; alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 6I ) S SR 56 ;
  • R 28 is alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S -OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ; -(CH 2 ) O (CHR 6I ) S
  • R 29 is alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 ) O (CHR 61 ) S SR 56 ;
  • R 30 is H; alkyl; alkenyl; or aryl-lower alkyl;
  • R 31 is H; alkyl; alkenyl; -(CH 2 ) P (CHR 61 ) S OR 55 ; -(CH 2 ) P (CHR 61 ) S NR 33 R 34 ; -(CH 2 )p(CHR 61 ) s OCONR 33 R 75 ; -(CH 2 ) P (CHR 61 ) S NR 20 CONR 33 R 82 ;
  • R 32 is H; lower alkyl; or aryl-lower alkyl;
  • R 33 is H; alkyl, alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s NR 34 R 63 ; -(CH 2 ) m (CHR 61 ) s OCONR 75 R 82 ; -(CH 2 ) m (CHR 61 ) s NR 20 CONR 78 R 82 ;
  • R 34 is H; lower alkyl; aryl, or aryl-lower alkyl;
  • R 33 and R 34 taken together can form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -;
  • R 35 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR ⁇ l ) s NR 33 R 34 ;
  • R 36 is H, alkyl; alkenyl; -(CH 2 ) 0 (CHR 61 ) S OR 55 ; -(CH 2 ) P (CHR 61 ) S NR 33 R 34 ;
  • R 37 is H; F; Br; Cl; NO 2 ; CF 3 ; lower alkyl; -(CH 2 ) P (CHR 61 ) S OR 55 ; -(CH 2 ) P (CHR 61 ) S NR 33 R 34 ;
  • R 38 is H; F; Br; Cl; NO 2 ; CF 3 ; alkyl; alkenyl; -(CH 2 ) P (CHR 61 ) S OR 55 ;
  • R 39 is H; alkyl; alkenyl; or aryl-lower alkyl;
  • R 40 is H; alkyl; alkenyl; or aryl-lower alkyl;
  • R 41 is H; F; Br; Cl; NO 2 ; CF 3 ; alkyl; alkenyl; -(CH 2 ) P (CHR 61 ) S OR 55 ;
  • R 42 is H; F; Br; Cl; NO 2 ; CF 3 ; alkyl; alkenyl; -(CH 2 ) P (CHR 61 ) S OR 55 ;
  • R 43 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ⁇ NR 33 R 34 ;
  • R 44 is alkyl; alkenyl; -(CH 2 ) r (CHR 61 ) s OR 55 ; -(CH 2 ) r (CHR 61 ) s SR 56 ; -(CH 2 ) r (CHR 61 ) 5 NR 33 R 34 ;
  • R 45 is H; alkyl; alkenyl; -(CH 2 ) O (CHR 61 ) S OR 55 ; -(CH 2 J 0 (CHR 61 JsSR 56 ;
  • R 46 is H; alkyl; alkenyl; or -(CH 2 J 0 (CHR 61 J p C 6 H 4 R 8 ;
  • R 47 is H; alkyl; alkenyl; or -(CH 2 ) O (CHR 61 ) S OR 55 ;
  • R 48 is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;
  • R 49 is H; alkyl; alkenyl; -(CHR 61 ) S COOR 57 ; (CHR 6I ) S CONR 58 R 59 ; (CHR 61 ) S PO(OR 60 ) 2 ;
  • R 50 is H; lower alkyl; or aryl-lower alkyl;
  • R 51 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 J 5 SR 56 ; -(CH 2 ) ra (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ;
  • R 52 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 ) s SR 56 ; -(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ;
  • R 53 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) s OR 55 ; -(CH 2 ) m (CHR 61 J 8 SR 56 ; -(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; -(CH 2 ) ra (CHR 61 ) s OCONR 33 R 75 ;
  • R 54 is H; alkyl; alkenyl; -(CH 2 ) m (CHR 61 ) 8 OR 55 ; -(CH 2 J 1n (CHR 61 J 8 NR 33 R 34 ; -(CH 2 J 1n (CHR 61 J 8 OCONR 33 R 75 ; -(CH 2 J 1n (CHR 61 J 8 NR 20 CONR 33 R 82 ;
  • R 55 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH 2 ) m (CHR 61 ) s OR 57 ;
  • R 56 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CH 2 ) m (CHR 6I ) s OR 57 ; -(CH 2 ) m (CHR 61 ) s NR 34 R 63 ; -(CH 2 ) m (CHR 61 ) s OCONR 75 R 82 ;
  • R 57 is H; lower alkyl; lower alkenyl; aryl lower alkyl; or heteroaryl lower alkyl;
  • R 58 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl;
  • R 59 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; or
  • R 58 and R 59 taken together can form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) r ; or
  • R 60 is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;
  • R 61 is H, alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH 2 ) P OR 55 ;
  • R 62 is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower alkyl;
  • R 63 is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl;
  • R 34 and R 63 taken together can form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -;
  • R 64 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; -(CH 2 ) P (CHR 61 ) S OR 65 ; -(CH 2 ) P (CHR 61 ) S SR 66 ; or -(CH 2 ) P (CHR 6I ) S NR 34 R 63 ; -(CH 2 )P(CHR 61 ) S OCONR 75 R 82 ; -(CH 2 )P(CHR 61 ) S NR 20 CONR 78 R 82 ;
  • R 65 is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; -COR 57 ; -COOR 57 ; or -CONR 58 R 59 ;
  • R 66 is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl; heteroaryl-lower alkyl; or -
  • R 67 being H; Cl; Br; F; NO 2 ; -NR 34 COR 57 ; lower alkyl; or lower alkenyl; R 68 being H; Cl; Br; F; NO 2 ; -NR 34 COR 57 ; lower alkyl; or lower alkenyl; R 69 being H; Cl; Br; F; NO 2 ; -NR 34 COR 57 ; lower alkyl; or lower alkenyl; and R 70 being H; Cl; Br; F; NO 2 ; -NR 34 COR 57 ; lower alkyl; or lower alkenyl; with the proviso that at least two of R 67 , R 68 , R 69 and R 70 are H; and
  • Z is a chain of 12 ⁇ -amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chain, GIy or Pro, or of formula -A-CO-, or of formula -B-CO-, or of one of the types
  • R 71 is H; lower alkyl; lower alkenyl; -(CX 2 ) P (CHR 61 ) S OR 75 ; -(CX 2 ) P (CHR 61 ) S SR 75 ; -(CX 2 ) P (CHR 61 ) S NR 33 R 34 ; -(CX 2 ) P (CXR 61 ) S OCONR 33 R 75 ; -(CX 2 ) P (CHR 61 ) S NR 20 CONR 33 R 82 ;
  • R 72 is H; lower alkyl; lower alkenyl; -(CX 2 ) p (CHR 86 ) s OR 85 ; or
  • R 73 is -(CX 2 ) O R 77 ; -(CX 2 ) r O(CH 2 ) o R 77 ; -(CX 2 ) r S(CH 2 ) 0 R 77 ; or
  • XX 1 -CH 3 where XX is -O-; -NR 20 -, or -S-; u is 1-3, and t is 1-6;
  • R 75 is lower alkyl; lower alkenyl; or aryl-lower alkyl;
  • R 33 and R 75 taken together can form: -(CX 2 ) 2 . 6 -; -(CX 2 ) 2 O(CX 2 ) 2 -; -(CX 2 ) 2 S(CX 2 ) 2 -; or
  • -(CX 2 ) 2 NR 57 (CX 2 ) 2 -; R 75 and R 82 taken together can form: -(CX 2 ) 2 . 6 -; -(CX 2 ) 2 O(CX 2 ) 2 -; -(CX 2 ) 2 S(CX 2 ) 2 -; or
  • R 76 isH; lower alkyl; lower alkenyl; aryl-lower alkyl; -(CX 2 ) O OR 72 ; -(CX 2 ) O SR 72 ; -(CXz) 0 NR 33 R 34 ; -(CX 2 ) 0 OCONR 33 R 75 ; -(CX 2 ) o NR 20 CONR 33 R 82 ; -(CX 2 ) o COOR 75 ; -(CX 2 ) o CONR 58 R 59 ; -(CX 2 ) o PO(OR 60 ) 2 ; -(CX 2 ) P SO 2 R 62 ; or -(CX 2 ) o COR 64 ;
  • R 77 is -C 6 R 67 R 68 R 69 R 70 R 76 ; or a heteroaryl group of one of the formulae
  • R 78 is H; lower alkyl; aryl; or aryl-lower alkyl;
  • R 78 and R 82 taken together can form: -(CX 2 ) 2 . 6 -; -(CX 2 ) 2 O(CX 2 )2-; -(CXa) 2 S(CXa) 2 -; or
  • R 79 is H; lower alkyl; aryl; or aryl-lower alkyl; or
  • R 78 and R 79 taken together, can be -(CX 2 ) 2-7 -; -(CX 2 ) 2 O(CX 2 ) 2 -; or -(CX 2 ) 2 NR 57 (CX 2 ) 2 -; R 80 is H; or lower alkyl;
  • R 81 is H; lower alkyl; or aryl-lower alkyl
  • R 82 is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;
  • R 33 and R 82 taken together can form: -(CX 2 ) 2 . 6 -; -(CXz) 2 O(CXz) 2 -; -(CX 2 ) 2 S(CX 2 ) 2 -; or
  • R 83 is H; lower alkyl; aryl; or -NR 78 R 79 ;
  • R 84 is -(CX 2 ) m (CHR 61 ) s OH; -(CX 2 ) P CONR 78 R 79 ; -(CX 2 ) P NR 80 CONR 78 R 79 ;
  • R 85 is lower alkyl; or lower alkenyl; R 86 is H, alkyl; alkenyl; -(CX 2 ) P OR 85 ;-(CX 2 ) P SR 85
  • R 87 is H; alkyl; alkenyl; heteroaryl, aryl-lower alkyl; -(CX 2 ) P OR 55 ; -(CX 2 ) p OCONR 75 R 82 ; -(CX 2 ) P NR 20 CONR 78 R 82 ; -(CX 2 ) P COOR 57 , or -(CX 2 ) P PO(OR 60 ) 2 ;
  • X is H; or optionally halogen; with the proviso that in said chain of 12 ⁇ -amino acid residues Z the amino acid residues in positions 1 to 12 are, in a preferred embodiment:
  • P2 oftype D or oftype E;
  • P3 of type C or of type D, or the residue is GIy or Pro;
  • P4 of type C or oftype E or oftype F, or the residue is GIy or Pro;
  • P5 of type E or of type D or of type C, or the residue is GIy or Pro
  • - P6 of type E or of type F or of type C or of formula -A-CO-, or the residue is GIy or Pro
  • P7 of type C or of type E or of type F or of formula -B-CO-;
  • P8 of type D or of type C, or of Type F, or the residue is Pro;
  • P9 of type C or of type E or of type D or of type F;
  • - PlO of type E;
  • PI l of type C or of type F, or the residue is Pro or GIy
  • Pl 2 of type C or of type D or of type E or of type F, or the residue is Pro
  • P4 and P9 and/or P2 and Pl 1 taken together, can form a group of type H; and at P6, PlO and Pl 1 also D-isomers being possible; or, alternatively, but in a less preferred embodiment: Pl : of type C or of type D or of type E or of type F, or the residue is
  • P2 of type C or of type F, or the residue is Pro or GIy ;
  • P3 of type E
  • - P4 of type C or of type E or of type D or of type F;
  • P5 of type D or of type C, or of type F, or the residue is Pro;
  • P6 of type C or of type E or of type F or of formula -B-CO-;
  • P7 of type E or of type F or of type C or of formula -A-CO-, or the residue is GIy or Pro
  • - P8 of type E or of type D or of type C, or the residue is GIy or Pro
  • P9 of type C or of type E or of type F; or the residue is GIy or Pro;
  • PlO of type C or of type D, or the residue is GIy or Pro;
  • Pl 1 of type D or of type E;
  • P12 of type C or of type D or of type E or of type F, or the residue is Pro;
  • P4 and P9 and/or P2 and Pl 1, taken together, can form a group of type H; and at P2, P3, and P7 also D-isomers being possible;
  • ⁇ -hairpin peptidomimetics can be prepared by a process which comprises
  • X is an N-protecting group or, if
  • step (fa) coupling the product obtained in step (e) with an appropriately N-protected derivative of an amino acid of the general formula
  • the peptidomimetics of the present invention can be prepared by
  • step (b 1 ) removing the N-protecting group from the product obtained in step (a 1 ) or
  • the peptidomimetics of the present invention can also be enantiomers of the compounds of formula I. These enantiomers can be prepared by a modification of the above processes in which enantiomers of all chiral starting materials are used.
  • alkyl designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms, ioptionally substituted with halogen.
  • alkenyl designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds, optionally substituted with halogen.
  • lower designates radicals and compounds having up to 6 carbon atoms.
  • lower alkyl designates saturated, straight-chain or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl and the like.
  • aryl designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF 3 , NO 2 , lower alkyl or lower alkenyl.
  • heteroaryl designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and said ring(s) being optionally substituted; representative examples of such optionally substituted heteroaryl radicals are indicated hereinabove in connection with the definition of R 77 .
  • the structural element -A-CO- designates amino acid building blocks which in combination with the structural element -B-CO- form templates (al) and (a2).
  • Templates (a) through (p) constitute building blocks which have an N-terminus and a C-terminus oriented in space in such a way that the distance between those two groups may lie between 4.0-5.5A.
  • a peptide chain Z is linked to the C-terminus and the N-terminus of the templates (a) through (p) via the corresponding N- and C-termini so that the template and the chain form a cyclic structure such as that depicted in formula I.
  • template and peptide chain form a ⁇ -hairpin mimetic.
  • the ⁇ -hairpin conformation is highly relevant for the anti-bacterial activity of the ⁇ -hairpin mimetics of the present invention.
  • the ⁇ -hairpin stabilizing conformational properties of the templates (a) through (p) play a key role not only for the selective antibacterial activity but also for the synthetic processes defined hereinabove, as incorporation of the templates at the beginning or near the middle of the linear protected peptide precursors enhances cyclization yields significantly.
  • Building blocks A1-A69 belong to a class of amino acids wherein the N-terminus is a secondary amine forming part of a ring. Among the genetically encoded amino acids only proline falls into this class.
  • the configuration of building block Al through A69 is (D), and they are combined with a building block -B-CO- of (L)-configuration.
  • Preferred combinations for templates (al) are- D Al-CO- L B-CO- to D A69-CO- L B-CO-.
  • D Pro- L Pro constitutes the prototype of templates (al).
  • Mores preferred, but possible are combinations- L Al-CO- D B-CO- to L A69-CO- D B-CO- forming templates (a2).
  • L Pro- D Pro constitutes the prototype of template (a2).
  • building blocks -Al-CO- to -A69-CO- in which A has (D)- configuration are carrying a group R 1 at the ⁇ -position to the N-terminus.
  • the preferred values for R 1 are H and lower alkyl with the most preferred values for R 1 being H and methyl.
  • Al- A69 are shown in (D)- conflguration which, for R 1 being H and methyl, corresponds to the (R) -configuration.
  • this configuration may also have to be expressed as (S).
  • R 2 building blocks -Al-CO- to -A69-CO- can carry an additional substituent designated as R 2 to R 17 .
  • This additional substituent can be H, and if it is other than H, it is preferably a small to medium-sized aliphatic or aromatic group. Examples of preferred values for R 2 to R 17 are:
  • -R 2 H; lower alkyl; lower alkenyl; (CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); (CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); (CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • -R 3 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) ra SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75
  • R 4 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alky
  • R 5 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) O OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33
  • R 6 H; lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) 0 OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl
  • R 7 lower alkyl; lower alkenyl; -(CH 2 ) q OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) q SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) q NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 8 H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); (CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 9 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 10 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 11 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 12 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 13 lower alkyl; lower alkenyl; -(CH 2 ) q OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) q SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) q NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R u H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 )JSlR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 )W-; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl
  • R" lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CHz) 0 SR 56 (where R 36 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 )z-; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) r ; where R 57 : H; or lower alkyl); -(CH 2 ) Q OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R
  • R 16 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 )MS -(CH 2 ) 2 O(CHz) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) O OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken
  • R 17 lower alkyl; lower alkenyl; -(CH 2 ) q OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) q SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) q NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • building blocks Al to A69 the following are preferred: A5 with R 2 being H, A8, A A2222,, A A22f5, A38 with R 2 being H, A42, A47, and A50. Most preferred are building blocks of type A8':
  • R 20 is H or lower alkyl; and R 64 is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially those wherein R 64 is n-hexyl (A8'-l); n-heptyl (A8'-2); 4- (phenyl)benzyl (A8'-3); diphenylmethyl (A8'-4); 3-amino-propyl (A8'-5); 5-amino-pentyl (A8 ?
  • Building block A70 belongs to the class of open-chain ⁇ -substituted ⁇ -amino acids, building blocks A71 and A72 to the corresponding ⁇ -amino acid analogues and building blocks A73- A104 to the cyclic analogues of A70.
  • Such amino acid derivatives have been shown to constrain small peptides in well defined reverse turn or U-shaped conformations (C. M. Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander, Biopolymers 1983, 22, 2577).
  • Such building blocks or templates are ideally suited for the stabilization of ⁇ - hairpin conformations in peptide loops (D. Obrecht, M. Altorfer, J. A.
  • templates (al) can also consist of -A70-CO- to A104-CO- where building block A70 to Al 04 is of either (D)- or (L)-configuration, in combination with a building block -B-CO- of (L)- configuration.
  • Preferred values for R 20 in A70 to A104 are H or lower alkyl with methyl being most preferred.
  • Preferred values for R 18 , R 19 and R 21 -R 29 in building blocks A70 to A104 are the following: - R 18 : lower alkyl.
  • R 19 lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CHa) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) P OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33
  • R 21 H; lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) 0 OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl;
  • R 22 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 35 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) 0 OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R
  • R 23 H; lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 W; -(CH 2 ) 2 O(CH 2 ) r ; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) 0 OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and
  • R 25 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2-6 -; -(CH 2
  • R 26 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2-6 -; -
  • R 82 (where R 20 : H; or lower lower alkyl; R 33 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 33 and R 82 taken together form: -(CH 2 ) 2 .
  • R 25 and R 26 taken together can be -(CH 2 ) 2 - 6 -; -(CH 2 )2 ⁇ (CH 2 )2-; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl).
  • R 27 H; lower alkyl; lower alkenyl; -(CH 2 ) 0 OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 28 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 29 lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) O OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33
  • R s H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34
  • R 33 lower alkyl; or lower alkenyl
  • R 34 H; or lower alkyl
  • R 33 and R 34 taken together form: -(CH 2 ) M S -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) O OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl;
  • R 75 lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 O(CH 2 ) 2 -;
  • R 30 H, methyl.
  • R 3J H; lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R" H, methyl. - R 33 : lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 34 R 63 (where R 34 : lower alkyl; or lower alkenyl; R 63 : H; or lower alkyl; or R 34 and R 63 taken together form: -(CH 2 ) 2 .
  • R 78 R 82 (where R 20 : H; or lower lower alkyl; R 78 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 78 and R 82 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 O(CH 2 ) r ; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl);
  • R 20 H; or lower alkyl
  • R 64 lower alkyl; or lower alkenyl
  • R 34 H; or lower alkyl.
  • R 35 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 82 (where R 20 : H; or lower lower alkyl; R 33 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 33 and R 82 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl);
  • R 20 H; or lower alkyl
  • R 64 lower alkyl; or lower alkenyl
  • R 36 lower alkyl; lower alkenyl; or aryl-lower alkyl.
  • R 37 H; lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or
  • R 33 and R 34 taken together form: -(CH 2 W; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) P OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 . 6 -;
  • R 82 (where R 20 : H; or lower alkyl; R 33 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 33 and R 82 taken together form: -(CH 2 ) 2 .
  • R 38 H; lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) P OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 78 taken together form: -(CH 2 ) 2 .
  • R 39 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m N(R 20 )COR 64 (where: R 20 : H; or lower alkyl; R 64 : lower alkyl; or lower alkenyl); -(CH 2 ) O COOR 57 (where R 57 : lower alkyl; or lower alkenyl); -(CH 2 ) 0 CONR 58 R 59 (where R 58 : lower alkyl; or lower alkenyl; and R 59 : H; lower alkyl; or R 58 and R 59 taken together form: -(CH 2 ) 2 .
  • R 10 lower alkyl; lower alkenyl; or aryl-lower alkyl.
  • R" H; lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 42 H; lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) P OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2-6 -; -(CH 2 )
  • R 43 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 )JMR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) M -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) r ; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl
  • R 44 lower alkyl; lower alkenyl; -(CH 2 ) P OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) P SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) P NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 3 taken together form: -(CH 2 ) M S -(CH 2 ) 2 O(CH 2 ) r ; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) P OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R
  • R 45 H; lower alkyl; lower alkenyl; -(CH 2 ) O OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) O SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) O NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 46 H; lower alkyl; lower alkenyl; -(CH 2 ) S OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) S SR 56 (where R 56 : lower alkyl; or lower alkenyl); -(CH 2 ) S NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 W; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) S OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R
  • R 57 H; or lower alkyl
  • R 8 H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy
  • R 47 H; or OR 55 (where R 55 : lower alkyl; or lower alkenyl).
  • R 48 H; or lower alkyl.
  • R 49 H;lower alkyl; -(CH 2 ) 0 COOR 57 (where R 57 : lower alkyl; or lower alkenyl);
  • R 58 lower alkyl; or lower alkenyl; and R 59 : H; lower alkyl; or R 58 and R 59 taken together form: -(CH 2 ) 2 . 6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or
  • R 57 H; or lower alkyl
  • R 8 H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy
  • R 50 H; methyl.
  • R 51 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 82 (where R 20 : H; or lower lower alkyl; R 33 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 33 and R 82 taken together form: -(CH 2 ) 2-6 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl);
  • R 20 H; or lower alkyl
  • R 64 lower alkyl; or lower alkenyl
  • R 52 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 ) m NR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 ) 2 .
  • R 82 (where R 20 : H; or lower lower alkyl; R 33 : H; or lower alkyl; or lower alkenyl; R 82 : H; or lower alkyl; or R 33 and R 82 taken together form: -(CH 2 ) 2-5 -; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; R 57 : H; or lower alkyl);
  • R 20 H; or lower alkyl
  • R 64 lower alkyl; or lower alkenyl
  • R 53 H; lower alkyl; lower alkenyl; -(CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl); -(CH 2 )JSTR 33 R 34 (where R 33 : lower alkyl; or lower alkenyl; R 34 : H; or lower alkyl; or R 33 and R 34 taken together form: -(CH 2 W; -(CH 2 ) 2 O(CH 2 ) 2 -; -(CH 2 ) 2 S(CH 2 ) 2 -; or -(CH 2 ) 2 NR 57 (CH 2 ) 2 -; where R 57 : H; or lower alkyl); -(CH 2 ) m OCONR 33 R 75 (where R 33 : H; or lower alkyl; or lower alkenyl; R 75 : lower alkyl; or R 33 and R 75 taken together form: -(CH 2 ) 2 .
  • R 54 lower alkyl; lower alkenyl; or aryl-lower alkyl.
  • building blocks A70 to Al 04 the following are preferred: A74 with R 22 being H, A75, A76, A77 with R 22 being H, A78 and A79.
  • the building block -B-CO- within templates (al) and (a2) designates an L-amino acid residue.
  • Preferred values for B are: -NR 20 CH(R 71 )- and enantiomers of groups A5 with R 2 being H, A8, A22, A25, A38 with R 2 being H, A42, A47, and A50. Most preferred are
  • phenylbenzyl (A8"-23); diphenylmethyl (A8"-24); 3-amino-propyl (A8"-25); 5- amino-pentyl (A8"-26); methyl (A8"-27); ethyl (A8"-28); isopropyl (A8"-29); isobutyl (A8"-30); n-propyl (A8"-31); cyclohexyl (A8"-32); cyclohexylmethyl (A8"-33); n- butyl (A8"-34); phenyl (A8"-35); benzyl (A8"-36); (3-indolyl)methyl (A8"-37); 2-(3- indolyl)ethyl (A8"-38); (4-phenyl)phenyl (A8"-39); n-nonyl (A8"-40); CH 3 -OCH 2 CH 2 -
  • the peptidic chain Z of the ⁇ -hairpin mimetics described herein is generally defined in terms of amino acid residues belonging to one of the following groups: - Group C -NR 20 CH(R 72 )CO-; "hydrophobic: small to medium-sized"
  • amino acid residues in chain Z can also be of formula -A-CO- or of formula -B-CO- wherein A and B are as defined above.
  • GIy can also be an amino acid residue in chain Z
  • Pro can be an amino acid residue in chain Z, too, with the exception of positions where interstrand linkages (H) are possible.
  • Group C comprises amino acid residues with small to medium-sized hydrophobic side chain groups according to the general definition for substituent R 72 .
  • a hydrophobic residue refers to an amino acid side chain that is uncharged at physiological pH and that is repelled by aqueous solution.
  • these side chains generally do not contain hydrogen bond donor groups, such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas.
  • ethers such as ethers, thioethers, esters, tertiary amides, alkyl- or aryl phosphonates and phosphates or tertiary amines.
  • Genetically encoded small-to-medium-sized amino acids include alanine, isoleucine, leucine, methionine and valine.
  • Group D comprises amino acid residues with aromatic and heteroaromatic side chain groups according to the general definition for substituent R 73 .
  • An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated ⁇ -electron system (aromatic group).
  • hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines.
  • Genetically encoded aromatic amino acids include phenylalanine and tyrosine.
  • a heteroaromatic amino acid residue refers to a hydrophobic amino acid having a side chain containing at least one ring having a conjugated ⁇ -system incorporating at least one heteroatom such as (but not limited to) O, S and N according to the general definition for substituent R 77 .
  • residues may contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates -and phosphates or tertiary amines.
  • Hydro bond donor groups such as (but not limited to) primary and secondary amides, primary and secondary amines and the corresponding protonated salts thereof, thiols, alcohols, phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptor groups such as (but not limited to) ethers, thioethers, esters, tetriary amides, alkyl- or aryl phosphonates
  • Group E comprises amino acids containing side chains with polar-cationic, acylamino- and urea-derived residues according to the general definition for substituen R 74 .
  • Polar-cationic refers to a basic side chain which is protonated at physiological pH.
  • Genetically encoded polar-cationic amino acids include arginine, lysine and histidine. Citrulline is an example for an urea derived amino acid residue.
  • Group F comprises amino acids containing side chains with polar-non-charged or anionic residues according to the general definition for substituent R 84 .
  • a polar-non-charged or anionic residue refers to a hydrophilic side chain that is uncharged and, respectively anionic at physiological pH (carboxylic acids being included), but that is not repelled by aqueous solutions.
  • Such side chains typically contain hydrogen bond donor groups such as (but not limited to) primary and secondary amides, carboxyclic acids and esters, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas. These groups can form hydrogen bond networks with water molecules.
  • polar-non-charged amino acids include asparagine, cysteine, glutamine, serine and threonine, but also aspartic acid and glutamic acid.
  • Group H comprises side chains of preferably (L)-amino acids at opposite positions of the ⁇ - strand region that can form an interstrand linkage.
  • the most widely known linkage is the disulfide bridge formed by cysteines and homo-cysteines positioned at opposite positions of the ⁇ -strand.
  • Various methods are known to form disulfide linkages including those described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart et al. , Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company, III., 1984; Ahmed et al. J. Biol. Chem.
  • disulfide linkages can be prepared using acetamidomethyl (Acm)- protective groups for cysteine.
  • a well established interstrand linkage consists in linking ornithines and lysines, respectively, with glutamic and aspartic acid residues located at opposite ⁇ -strand positions by means of an amide bond formation.
  • Preferred protective groups for the side chain amino- groups of ornithine and lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic and glutamic acid.
  • interstrand linkages can also be established by linking the amino groups of lysine and ornithine located at opposite ⁇ -strand positions with reagents such as N,N-carbonylimidazole to form cyclic ureas.
  • positions for interstrand linkages are positions P4 and P 9 and/or P2 and Pl 1 taken together.
  • Such interstrand linkages are known to stabilize the ⁇ -hairpin conformations and thus constitute an important structural element for the design of ⁇ -hairpin mimetics.
  • amino acid residues in chain Z are those derived from natural ⁇ -amino acids.
  • amino acids which, or the residues of which, are suitable for the purposes of the present invention, the abbreviations corresponding to generally adopted usual practice:
  • ⁇ -amino acids which, or the residues of which, are suitable for the purposes of the present invention include: C Ciitt L-Citrulline
  • arly preferrei i residues for group D are:
  • residues for group E are Arg L-Arginine Lys L-Lysine
  • residues for group F are Asn L-Asparagine
  • the peptidic chain Z within the ⁇ -hairpin mimetics of the invention comprises 12 amino acid residues.
  • the positions Pl to P12 of each amino acid residue in the chain Z are unequivocally defined as follows: Pl represents the first amino acid in the chain Z that is coupled with its N-terminus to the C-terminus of the templates (b)-(p), or of group -B-CO- in template (al), or of group -A-CO- in template (a2); and P12 represents the last amino acid in the chain Z that is coupled with its C-terminus to the N-terminus of the templates (b)-(p), or of group -A-CO- in template (al), or of group -B-CO- in template (a2).
  • Each of the positions Pl to P12 will preferably contain an amino acid residue belonging to one of the above types C, D, E, F, H, or of formula -A-CO- or of formula -B-CO-, or being GIy, or Pro as follows:
  • the ⁇ -amino acid residues in positions 1 to 12 of the chain Z are preferably: - Pl : of type C or of type D or of type E or of type F;
  • P3 of type C, or the residue is GIy or Pro;
  • P4 of type C or of type E or of type F, or the residue is GIy or Pro;
  • P5 of type E, or the residue is GIy or Pro
  • - P6 of type E, of type C or of type F or of formula -A-CO-, or the residue is GIy or Pro
  • P7 of type C or of type E or of type F or of formula -B-CO-;
  • P8 of type D, or of type F;
  • P9 oftype E or oftype F or oftype C;
  • PI l of type F or of type C, or the residue is GIy or Pro
  • - P12 of type C or of type D or of type E, or of type F; or
  • P4 and P9 and/or P2 and Pl 1 taken together, can form a group of type H; and at P6, PlO and PI l also D-isomers being possible; or, alternatively, within the less preferred embodiment mentioned earlier herein above: - Pl : of type C or of type D or of type E, or of type F;
  • P2 of type F or of type C, or the residue is GIy or Pro;
  • P4 of type E or of type F or of type C;
  • P5 of type D, or of Type F
  • - P6 of type C or of type E or of type F or of formula -B-CO-;
  • P7 of type C or of type F or of formula -A-CO-, or the residue is GIy or Pro;
  • P8 of type E, or the residue is GIy or Pro;
  • P9 of type C or of type E or of type F, or the residue is GIy or Pro
  • - PlO of type C, or the residue is GIy or Pro
  • P12 of type C or of type D or of type E or of type F; or
  • P4 and P9 and/or P2 and PI l taken together, can form a group of type H; and at P2, P3, and P7 also D-isomers being possible.
  • the ⁇ -amino acid residues in positions 1 to 12 are most preferably: Pl : Ala, Cit, Thr, Thr, Asp, GIu;
  • P2 Trp, Tyr; - P3: Ile, Val, Nle, Chg, Cha;
  • P7 His, Lys, GIn, Dab;
  • Pl 1 Ala, Abu, Thr, GIy, Pro, Hse, lie, Nva, 0 AIa, 0 VaI, Aib, NIe, Chg,
  • P12 Dab, Lys, GIn, Ser; at P6, PlO and Pl 1 are D-Isomers being possible.
  • Particularly preferred ⁇ -hairpin peptidomimetics of the invention include those described in Examples 1, 2, 6, 16, 19, 22, 24, 25, 28, 29, 32, 35, 40, 41, 49, 50.
  • the processes of the invention can advantageously be carried out as parallel array syntheses to yield libraries of template-fixed ⁇ -hairpin peptidomimetics of the above general formula I.
  • Such parallel syntheses allow one to obtain arrays of numerous (normally 24 to 192, typically 96) compounds of general formula I in high yields and defined purities, minimizing the formation of dimeric and polymeric by-products.
  • the proper choice of the functionalized solid-support (i.e. solid support plus linker molecule), templates and site of cyclization play thereby key roles.
  • the functionalized solid support is conveniently derived from polystyrene crosslinked with, preferably 1-5%, divinylbenzene; polystyrene coated with polyethyleneglycol spacers (Tentagel R ); and polyacrylamide resins (see also Obrecht, D.; Villalgordo, J. -M, "Solid- Supported Combinatorial and Parallel Synthesis of Small-Molecular- Weight Compound Libraries", Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).
  • the solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures.
  • a linker i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures.
  • linkers i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures.
  • Type 1 linkers are designed to release the amide group under acidic conditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790).
  • Linkers of this kind form amides of the carboxyl group of the amino acids; examples of resins functionalized by such linker structures include 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] PS resin, 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] -4- methylbenzydrylamine PS resin (Rink amide MBHA PS Resin), and 4-[(((2,4- dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) aminomethyl] benzhydrylamine PS-resin (Rink amide BHA PS resin).
  • the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 4- (((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.
  • Type 2 linkers are designed to eventually release the carboxyl group under acidic conditions.
  • Linkers of this kind form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin R linker), 4-(2,4-dimethoxyphenyl- hydroxymethyl)-phenoxy (Rink linker), 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityl and 2-chlorotrityl.
  • the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 2-chlorotrityl linker.
  • a number of reaction vessels (normally 24 to 192, typically 96), equal to the total number of compounds to be synthesized by the parallel method, are loaded with 25 to 1000 mg, preferably 100 mg, of the appropriate functionalized solid support, preferably 1 to 3% cross- linked polystyrene or Tentagel resin.
  • the solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE), isopropylalcohol and the like.
  • Solvent mixtures containing as at least one component a polar solvent are beneficial for ensuring high reactivity and solvation of the resin-bound peptide chains ( Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991, 113, 4202-4207).
  • Suitable protecting groups for amino acids and, respectively, for their residues are, for example,
  • guanidino group (as is present e. g. in the side-chain of arginine)
  • Ts tosyl i. e. p-toluenesulfonyl
  • the 9-fluorenylmethoxycarbonyl- (Fmoc)-protected amino acid derivatives are preferably used as the building blocks for the construction of the template-fixed ⁇ -hairpin loop mimetics of formula I.
  • For the deprotection, i. e. cleaving off of the Fmoc group 20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.
  • the quantity of the reactant i. e. of the amino acid derivative, is usually 1 to 20 equivalents based on the milliequivalents per gram (meq/g) loading of the functionalized solid support (typically 0.1 to 2.85 meq/g for polystyrene resins) originally weighed into the reaction tube. Additional equivalents of reactants can be used, if required, to drive the reaction to completion in a reasonable time.
  • the reaction tubes, in combination with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together. Gas flow through the manifold is initiated to provide a controlled environment, for example, nitrogen, argon, air and the like. The gas flow may also be heated or chilled prior to flow through the manifold.
  • Heating or cooling of the reaction wells is achieved by heating the reaction block or cooling externally with isopropanol/dry ice and the like to bring about the desired synthetic reactions. Agitation is achieved by shaking or magnetic stirring (within the reaction tube).
  • the preferred workstations are Labsource's Combi-chem station and MultiSyn Tech's-Syro synthesizer.
  • Amide bond formation requires the activation of the ⁇ -carboxyl group for the acylation step.
  • this activation is being carried out by means of the commonly used carbodiimides such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067- 1068) or diisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res. Commun.1976, 73, 336-342), the resulting dicyclohexylurea and diisopropylurea is insoluble and, respectively, soluble in the solvents generally used.
  • DCC dicyclohexylcarbodiimide
  • DIC Diisopropylcarbodiimide
  • 1-hydroxybenzotriazole (HOBt, Konig & Geiger, Chem. Ber 1970, 103, 788-798) is included as an additive to the coupling mixture.
  • HOBt prevents dehydration, suppresses racemization of the activated amino acids and acts as a catalyst to improve the sluggish coupling reactions.
  • Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-l-yl-oxy-tris-(dimethylamino)-phos ⁇ honium hexafluorophosphate (BOP, Castro et al., Tetrahedron Lett 1975, 14, 1219-1222; Synthesis, 1976, 751-752), or benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate (Py-BOP, Coste et al., Tetrahedron Lett.
  • BOP benzotriazol-l-yl-oxy-tris-(dimethylamino)-phos ⁇ honium hexafluorophosphate
  • Py-BOP Coste et al., Tetrahedron Lett.
  • DPPA diphenoxyphosphoryl azide
  • TATU O-(7- aza-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • HATU O-(7-aza- benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HOAt Carpino et al., Tetrahedron Lett. 1994, 35, 2279-2281
  • reaction wells are filled with solvent (preferably 5 ml), the reaction tubes, in combination with the holder block and manifold, are immersed and agitated for 5 to 300 minutes, preferably 15 minutes, and drained by gravity followed by gas pressure applied through the manifold inlet (while closing the outlet) to expel the solvent; 2) The manifold is removed from the holder block, aliquots of solvent
  • reaction tubes preferably 5 ml
  • a filter preferably 5 ml
  • Both of the above washing procedures are repeated up to about 50 times (preferably about 10 times), monitoring the efficiency of reagent, solvent and by-product removal by methods such as TLC, GC, or inspection of the washings.
  • IPegK IPegK
  • SPegK a solution of 5 equivalents of HATU (N-[(dimethylamino)-lH- l,2,3-triazolo[4,5- ⁇ ]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide) in dry DMF and a solution of 10 equivalents of DIPEA (Diisopropyl ethaylamine) in dry DMF and 5 equivalents of 2-[2-(2-methoxyethoxy)ethoxy] acetic acid (IPeg) and, respectively, 2-(2-methoxyethoxy)acetic acid (sPeg), is applied to the liberated amino group of the appropiate amino acid side chain for 3 h.
  • DIPEA Diisopropyl ethaylamine
  • Interstrand linkages and their formation have been discussed above, in connection with the explanations made regarding groups of the type H which can, for example, be disulfide bridges formed by cysteine and homocysteine residues at opposite positions of the ⁇ -strand; or lactam bridges formed by glutamic and aspartic acid residues linking ornithine and, respectively, lysine residues, or by glutamic acid residues linking 2,4-diaminobutyric acid residues located at opposite ⁇ -strand positions by amide bond formation.
  • groups of the type H which can, for example, be disulfide bridges formed by cysteine and homocysteine residues at opposite positions of the ⁇ -strand; or lactam bridges formed by glutamic and aspartic acid residues linking ornithine and, respectively, lysine residues, or by glutamic acid residues linking 2,4-diaminobutyric acid residues located at opposite ⁇ -strand positions by amide bond formation.
  • a solution of 10 equivalents of iodine solution is applied in DMF or in a mixture OfCH 2 Cl 2 /MeOH for 1.5 h which is repeated for another 3h with a fresh iodine solution after filtering of the iodine solution, or in a mixture of DMSO and acetic acid solution, buffered with 5% with NaHCOsto pH 5-6 for 4h, or in water after having been adjusted to pH 8 with ammonium hydroxide solution by stirring for 24h or ammonium acetate buffer adjusted to pH 8 in the presence of air, or in a solution of NMP and tri-n- butylphosphine (preferably 50 eq.).
  • Detachment of the fully protected linear peptide from the solid support is achieved by immersion of the reaction tubes, in combination with the holder block and manifold, in reaction wells containing a solution of the cleavage reagent (preferably 3 to 5 ml). Gas flow, temperature control, agitation and reaction monitoring are implemented as described above and as desired to effect the detachment reaction.
  • the reaction tubes, in combination with the holder block and manifold are disassembled from the reservoir block and raised above the solution level but below the upper lip of the reaction wells, and gas pressure is applied through the manifold inlet (while closing the outlet) to efficiently expel the final product solution into the reservoir wells.
  • the resin remaining in the reaction tubes is then washed 2 to 5 times as above with 3 to 5 ml of an appropriate solvent to extract (wash out) as much of the detached product as possible.
  • the product solutions thus obtained are combined, taking care to avoid cross-mixing.
  • the individual solutions/extracts are then manipulated as needed to isolate the final compounds. Typical manipulations include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or additional reactions in solution.
  • the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent.
  • a solvent which is not miscible with water such as DCM
  • the fully protected peptide derivative is treated with 95% TFA, 2.5% H 2 O, 2.5% TIS or another combination of scavengers for effecting the cleavage of protecting groups.
  • the cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2.5 hours.
  • the volatiles are evaporated to dryness and the crude peptide is dissolved in 20% AcOH in water and extracted with isopropyl ether or other solvents which are suitable therefor.
  • the aqueous layer is collected and evaporated to dryness, and the fully deprotected cyclic peptide derivative of formula I is obtained as end-product.
  • this peptide derivative can be used directly for biological assays, or it has to be further purified, for example by preparative HPLC.
  • the detachment, cyclisation and complete deprotection of the fully protected peptide from the solid support can be achieved manually in glass vessels.
  • the ⁇ -hairpin peptidomimetics of the invention can be used in a wide range of applications in order to inhibit the growth of or to kill microorganisms.
  • they can be used to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa.
  • ⁇ -hairpin peptidomimetics of the invention can also be used to treat or prevent diseases related to microbial infection in plants and animals.
  • the ⁇ -hairpin peptidomimetics can be added to the desired material singly, as mixtures of several ⁇ -hairpin peptidomimetics or in combination with other antimicrobial agents.
  • the ⁇ -hairpin peptidomimetics may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.
  • infections related to respiratory diseases such as cystic fibrosis, emphysema and asthma
  • infections related to skin or soft tissue diseases such as surgical wounds, traumatic wounds and burn wounds
  • infections related to gastrointestinal diseases such as epidemic diarrhea, necrotizing enterocolitis and typhlitis
  • infections related to eye diseases such as keratitis and endophthalmitis
  • infections related to ear diseases such as otitis, infections related to CNS diseases such as brain abscess and meningitis
  • infections related to bone diseases such as osteochondritis and osteomyelitis
  • infections related to cardiovascular diseases such as endocartitis and pericarditis
  • gastrourinal diseases such as epididymitis, prostatitis and urethritis
  • the ⁇ -hairpin peptidomimetics can be administered singly, as mixtures of several ⁇ -hairpin peptidomimetics, in combination with other antimicrobial or antibiotic agents, or anti cancer agents, or anti
  • compositions comprising ⁇ -hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active ⁇ -hairpin peptidomimetics into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
  • ⁇ -hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
  • the ⁇ -hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer.
  • the solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the ⁇ -hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
  • the compounds can be readily formulated by combining the active ⁇ - hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the ⁇ -hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion of a patient to be treated.
  • suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
  • desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc.
  • flavoring agents, preservatives, coloring agents and the like may be added.
  • the composition may take the form of tablets, lozenges, etc. formulated as usual.
  • the ⁇ -hairpin peptidomimetics of the invention are conveniently delivered in form of an aeorosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifmoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • a suitable propellant e.g. dichlorodifmoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • the dose unit may be determined by providing a valve to deliver a metered amount.
  • gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the ⁇ -hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.
  • the ⁇ -hairpin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection.
  • the ⁇ -hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.
  • ⁇ -hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.
  • ⁇ -hairpin pepdidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free base forms.
  • ⁇ -hairpin peptidomimetics of the invention will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application.
  • an antimicrobially effective amount of a ⁇ -hairpin peptidomimetic of the invention, or a composition thereof is applied or added to the material to be desinfected or preserved.
  • antimicrobially effective amount is meant an amount of a ⁇ -hairpin peptidomimetic of the invention, or a composition thereof, that inhibits the growth of, or is lethal to, a target microbe population. While the antimicrobially effective amount will depend on a particular application, for use as desinfectants or preservatives the ⁇ -hairpin peptidomimetics of the invention, or compositions thereof, are usually added or applied to the material to be desinfected or preserved in relatively low amounts.
  • the ⁇ -hairpin peptidomimetics of the invention comprise less than about 5% by weight of a desinfectant solution or material to be preserved, preferably less than 1% by weight and more preferably less than 0.1% by weight.
  • a desinfectant solution or material to be preserved preferably less than 1% by weight and more preferably less than 0.1% by weight.
  • An ordinary skilled expert will be able to determine antimicrobially effective amounts of particular ⁇ -hairpin pepdidomimetics of the invention for particular applications without undue experimentation using, for example, the in vitro assays provided in the examples.
  • the ⁇ - hairpin pepidomimetics of the invention, or compositions thereof are administered or applied in a therapeutically effective amount.
  • therapeutically effective amount is meant an amount effective in ameliorating the symptoms of, or in ameliorating, treating or preventing microbial infections or diseases related thereto. Determination of a therapeutically effective amount is well within the capacities of those skilled in the art, especially in view of the detailed disclosure provided herein.
  • a therapeutically effective dose can be determined using, for example, the in vitro assays provided in the examples.
  • the treatment may be applied while the infection is visible, or even when it is not visible.
  • An ordinary skilled expert will be able to determine therapeutically effective amounts to treat topical infections without undue experimentation.
  • a therapeutically effective dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models to achieve a circulating ⁇ -hairpin peptidomimetic concentration range that includes the IC 50 as determined in the cell culture (i.e. the concentration of a test compound that is lethal to 50% of a cell culture), the MIC, as determined in cell culture (i.e. the concentration of a test compound that is lethal to 100% of a cell culture).
  • IC 50 as determined in the cell culture
  • the MIC as determined in cell culture
  • Such information can be used to more accurately determine useful doses in humans.
  • Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art. One having ordinary skills in the art could readily optimize administration to humans based on animal data.
  • Dosage amount for applications as antimicrobial agents may be adjusted individually to provide plasma levels of the ⁇ -hairpin peptidomimetics of the invention which are sufficient to maintain the therapeutic effect.
  • Therapeutically effective serum levels may be achieved by administering multiple doses each day.
  • the effective local concentration of the ⁇ - hairpin peptidomimetics of the invention may not be related to plasma concentration.
  • One having the skills in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • the amount of ⁇ -hairpin peptidomimetics administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgement of the prescribing physician.
  • the antimicrobial therapy may be repeated intermittently while infections are detectable or even when they are not detectable.
  • the therapy may be provided alone or in combination with other drugs, such as for example antibiotics or other antimicrobial agents.
  • a therapeutically effective dose of the ⁇ -hairpin peptidomimetics described herein will provide therapeutic benefit without causing substantial toxicity.
  • Hemolysis of red blood cells is often employed for assessment of toxicity of related compounds such as protegrin or tachyplesin. Values are given as %-lysis of red blood cells observed at a concentration of lOO ⁇ g/ml. Typical values determined for cationic peptides such as protegrin and tachyplesin range between 30-40% with average MIC-values of 1- 5 ⁇ g/ml over a wide range of pathogens. Normally, ⁇ -hairpin peptidomimetics of the invention will show hemolysis in a range of 0.5-10%, often in a range of 1-5%, at activity levels comparable to those mentioned above for protegrin and tachyplesin. Thus preferred compounds exhibit low MIC-values and low %-hemolysis of red blood cells observed at a concentration of lOO ⁇ g/ml.
  • Toxicity of the ⁇ -hairpin peptidomimetics of the invention herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) or the LDioo (the dose lethal to 100% of the population).
  • the dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans.
  • the dosage of the ⁇ -hairpin peptidomimetics of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity.
  • the dosage may vary within the range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e.g. Fingl et al. 1975, In : The Pharmacological Basis of Titer apeutics, Ch.1, p.l).
  • HOBt 1-hydroxybenzotriazole
  • DIEA diisopropylethylamine
  • HOAT 7-aza- 1 -hydroxybenzotriazole
  • HATU O-(7-aza-benzotriazole-l-yl)-N,N,N',N'-tetramethyluronoium hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35, 2279-2281).
  • the resin was shaken (CH 2 Cl 2 /MeOH/DIEA : 17/2/1), 30 ml for 30 min; then washed in the following order with CH 2 Cl 2 (Ix), DMF (Ix), CH 2 Cl 2 (Ix), MeOH (Ix), CH 2 Cl 2 (Ix), MeOH (Ix), CH 2 Cl 2 (2x), Et 2 O (2x) and dried under vacuum for 6 hours.
  • Loading was typically 0.6-0.7 mMol/g.
  • the following preloaded resin was prepared: Fmoc-Pro-2-chlorotritylresin.
  • the synthesis was carried out using a Syro-peptide synthesizer (Multisyntech) using 24 to 96 reaction vessels. In each vessel were placed 60 mg (weight of the resin before loading) of the above resin. The following reaction cycles were programmed and carried out:
  • Steps 3 to 6 are repeated to add each amino-acid.
  • Aquity UPLC BEH C18 column (1.7 ⁇ m, 100 x 2.1 mm, cod. 186002352 - Waters) with the following solvents A (H 2 O + 0.1% TFA) and B (CH 3 CN + 0.085% TFA) and the gradient: 0 min: 95%A, 5%B; 0.2 min: 95%A 5%B; 4 min: 35%A, 65%B; 4.2 min: 5% A, 95%B; 4.25 min: 95%A, 5%B; 4.9 min: 95%A, 5%B.
  • the resin was suspended in 1 ml (0.39 mMol) of 1% TFA in CH 2 Cl 2 (v/v) for 3 minutes and filtered, and the filtrate was neutralized with ImI (1.17 mMol, 3eq.) of 20% DIEA in CH 2 Cl 2 (v/v). This procedure was repeated twice to ensure completion of the cleavage.
  • the resin was washed with 2ml OfCH 2 Cl 2 .
  • the CH 2 Cl 2 layer was evaporated to dryness.
  • the fully protected linear peptide was solubilised in 8 ml of dry DMF. Then 2 eq. of HATU in dry DMF (ImI) and 4 eq.
  • Examples 1-50 are shown in Table 1.
  • the peptides were synthesized starting with the amino acid L-Pro which was grafted to the resin.
  • Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared as described above.
  • the linear peptides were synthesized on solid support according to the procedure described above in the following sequence: Resin-Pro- D Pro-P12-Pl 1-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.
  • Ex. 1-50 were cleaved from the resin, cyclized, deprotected and purified as indicated by preparative reverse phase LC-MS.
  • HPLC-retention times were determined using the analytical methods as described above. Examples 1 to 39 were analysed with method I 1 for Examples 40-50 method 2 was used:
  • Ex. 1 (8.87), Ex. 2 (9.26), Ex. 3 (9.34), Ex. 4 (9.45), Ex. 5 (9.48), Ex. 6 (9.44), Ex. 7 (10.11), Ex.8 (9.99), Ex.9 (10.22), Ex.10 (9.76), Ex.11 (10.56), Ex.12 (11.37), Ex.13 (9.13), Ex.
  • Lyophilized peptides were weighed on a Microbalance (Mettler MT5) and dissolved in sterile water to a final concentration of 1 mg/ml unless stated otherwise. Stock solutions were kept at +4 0 C, light protected.
  • the selective antimicrobial activities of the peptides were determined in 96-well plates (Nunclon polystyrene) by the standard NCCLS broth microdilution method (see ref 1, below) with slight modifications. Innocula of the microorganisms were diluted into
  • cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells (CRL-1651) was determined using the MTT reduction assay [see ref. 2 and 3, below]. Briefly the method was as follows: HELA cells and COS-7 cells were seeded at 7.OxIO 3 and, respectively, 4.5x10 3 cells per well and grown in 96-well microtiter plates for 24 hours at 37°C at 5% CC" 2 . At this point, time zero (Tz) was determined by MTT reduction (see below). The supernatant of the remaining wells was discarded, and fresh medium and the peptides in serial dilutions of 12.5, 25 and 50 ⁇ M were dispensed into the wells.
  • peptide concentration was assayed in triplicate. Incubation of the cells was continued for 48 hours at 37°C at 5% CO 2 . Wells were then washed once with phosphate buffered saline (PBS) and subsequently 100 ⁇ l MTT reagent (0.5 mg/ml in medium RPMI1640 and, respectively, DMEM) were added to the wells. This was incubated at 37 0 C for 2 hours and subsequently the medium was aspirated and 100 ⁇ l isopropanol were added to each well. The absorbance at 595 nm of the solubilized product was measured (ODs 95 peptide). For each concentration averages were calculated from triplicates.
  • PBS phosphate buffered saline
  • MTT reagent 0.5 mg/ml in medium RPMI1640 and, respectively, DMEM
  • the percentage of growth was calculated as follows: (OD 59 5peptide-OD59 5 Tz-OD 595 Empty well) / (OD 595 Tz- OD 595 Em ⁇ ty well) x 100% and was plotted for each peptide concentration.
  • the LC 50 values Lethal Concentration, defined as the concentration that kills 50% of the cells
  • hRBC fresh hRBC were washed three times with phosphate buffered saline (PBS) by centrifugation for 10 min at 2000 x g. Peptides at a concentration of 100 ⁇ M were incubated with 20% v/v hRBC for 1 hour at 37 0 C. The final erythrocyte concentration was approximately 0.9xl0 9 cells per ml. A value of 0% and, respectively,. 100% cell lysis was determined by incubation of the hRBC in the presence of PBS alone and, respectively, 0.1% Triton X-100 in H 2 O.
  • PBS phosphate buffered saline
  • the filtrates in the receiver PP plate were analysed by LC/MS as follows: Column: Jupiter C18 (Phenomenex), mobile phases: (A) 0.1% formic acid in water and (B) acetonitrile, gradient: 5%-100% (B) in 2 minutes, electrospray ionization, MRM detection (triple quadrupole). The peak areas were determined and triplicate values were averaged. The binding was expressed in percent of the (filtered and not-filtered time point 0 min) control 1 and 2 by: 100-(100 x T 6 o/T 0 ). The average from these values was then calculated.
  • Example 1 Pharmacokinetic study after single intravenous (i.v.) and subcutaneous (s.c.) administration was performed for the compound of Example 1 ("Ex. 1").
  • CD-I mice (20- 25 g) were used in the study.
  • Physiological saline was used a vehicle.
  • the volume was 2 ml/kg i.v., and 5 ml/kg s.c. and the peptide Ex. 1 was injected to give a final intravenous dose of 1 mg/kg, and a subcutaneous dose of 5 mg/kg.
  • the plate containing eluates was introduced into the concentrator system and taken to dryness.
  • the residues were dissolved in 100 ⁇ L of formic acid 0.1%/acetonitrile, 95/5 (v/v) and analysed in the HPLC/MS on a reverse phase analytical column (Jupiter C 18, 50 x 2.0 mm, 5 ⁇ m, Phenomenex), using gradient elution (mobile phases A: 0.1% formic acid in water, B: Acetonitrile; from 5%B to 100%B in 2 min.).
  • Samples coming from animal treatments were pooled in order to obtain an appropriate volume for the extraction. If the total volume obtained was less than 0.2 ml the appropriate amount of "blank" mouse plasma was added in order to keep the matrix identical to the calibration curve. Samples were than spiked with IS and processed as described for the calibration curve.
  • the area under the curve AUC was calculated by the linear trapezoidal rule.
  • Elimination half-life was calculated by the linear regression on at least three data points during the elimination phase.
  • the time intervals selected for the half-life determinations were evaluated by the correlation coefficient (r 2 ), which should be at least above 0.85 and most optimally above 0.96.
  • r 2 correlation coefficient
  • the initial concentration at t zero was determined by extrapolation of the curve through the first two time points.
  • bioavailability after i.p. administration was calculated from the normalised AUCinf_D_obs ration after s.c. versus i.v. administration.
  • Ex. 1 After intravenous administration of Ex. 1 at a dose level of 1 mg/kg body weight, Ex. 1 followed intravenous kinetic characteristics. After PK analysis, Ex. 1 showed an extrapolated Ci n i t j a i of 2174 ng/ml and a C max observed of 1268 ng/ml at 5 min. Plasma levels rapidly decreased to 575 and 177 ng/ml at 15 min and 1 hour respectively. From 0.5 to 2 h plasma levels decreased with an elimination half-life of 0.53 h to 10.6 ng/ml at

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EP07700115A 2006-01-16 2007-01-15 Schablonenfixierte peptidomimetika Active EP1979374B1 (de)

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PL07700115T PL1979374T3 (pl) 2006-01-16 2007-01-15 Peptydomimetyki związane z matrycą
SI200730882T SI1979374T1 (sl) 2006-01-16 2007-01-15 Matriäśno fiksirani peptidomimetiki
CY20121100294T CY1117252T1 (el) 2006-01-16 2012-03-20 Πεπτιδομιμητικα προσδεδεμενα σε μια μητρα

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PCT/CH2006/000036 WO2007079597A1 (en) 2006-01-16 2006-01-16 Template - fixed peptidomimetics with antimicrobial activity
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EA200801710A1 (ru) 2009-02-27
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HK1175478A1 (en) 2013-07-05
BRPI0707144A2 (pt) 2011-04-19
WO2007079605A2 (en) 2007-07-19
KR101352829B1 (ko) 2014-02-17
PL1979374T3 (pl) 2012-07-31
CN101395173B (zh) 2013-03-13
IL192816A (en) 2013-06-27
KR20090010022A (ko) 2009-01-28
ATE538131T1 (de) 2012-01-15
CN101395173A (zh) 2009-03-25
EP1979374B1 (de) 2011-12-21
US9521846B2 (en) 2016-12-20
US10730912B2 (en) 2020-08-04
US20100240592A1 (en) 2010-09-23
US20170107259A1 (en) 2017-04-20
JP2009523713A (ja) 2009-06-25
AU2007204547A1 (en) 2007-07-19
US9538752B2 (en) 2017-01-10
NZ570245A (en) 2011-02-25
AU2007204547B2 (en) 2012-09-20
NO20083485L (no) 2008-10-14
WO2007079605A3 (en) 2007-08-30
US20140187472A1 (en) 2014-07-03
CN102796179A (zh) 2012-11-28
EA015991B1 (ru) 2012-01-30
HK1127957A1 (zh) 2009-10-09
IL192816A0 (en) 2009-02-11
SI1979374T1 (sl) 2012-06-29
JP5237826B2 (ja) 2013-07-17
PT1979374E (pt) 2012-03-29
DK1979374T3 (da) 2012-04-10
CA2637377C (en) 2016-03-22
US20140187471A1 (en) 2014-07-03
WO2007079597A1 (en) 2007-07-19
NO341875B1 (no) 2018-02-12
CY1117252T1 (el) 2017-04-26
US20140087994A1 (en) 2014-03-27
ZA200806564B (en) 2010-05-26
US8685922B2 (en) 2014-04-01
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